PHYTOMEDICINE
·
2025
·
IF 8.3
Yixu Wang,Jin Zhang,Sihan Xu,Junjie Li,Wenjuan Liu,Min Jiang,Gang Bai
Background Acute lung injury (ALI) is a critical pathophysiological response in various respiratory diseases characterized by alveolar damage and excessive inflammation. It can progress to acute respiratory distress syndrome, with current treatments showing limited efficacy and considerable side effects. Psoralen (Pso), derived from Psoralea corylifolia L., has anti-inflammatory properties, but its role in ALI remains fully elucidated. Purpose This study aimed to investigate the therapeutic effects of Pso on ALI, and to explore its therapeutic targets and mechanisms. Methods The therapeutic potential of Pso was assessed using a model of ALI induced by lipopolysaccharide (LPS). The direct target was investigated using alkynyl-Psoralen (A-Pso) for chemical proteomic analysis, and a series of molecular biology methods were used to explore the underlying mechanism. Results Pso treatment significantly alleviated LPS-induced lung injury in mice, targeted macrophages, and inhibited the LPS-induced activation of macrophages. Target-fishing experiments identified high-mobility group box-1 (HMGB1) as a direct target of Pso in macrophages. FTS and CETSA confirmed Pso binding to HMGB1, and LC-MS/MS analysis indicated a covalent interaction between Pso and Cys106 of HMGB1. Furthermore, Pso covalently targeted Cys106, affecting HMGB1 binding to TLR4 and downregulating the phosphorylation of NF-κB, indicating the inhibition of the TLR4/NF-κB signaling pathway both in macrophages and in lung tissues of ALI mice. These findings suggest that Pso exerts its therapeutic effects by covalently targeting HMGB1 in macrophages and modulating the TLR4/NF-κB signaling pathway. Conclusion This study not only found that Pso improves LPS-induced ALI inflammation by targeting macrophages, but also verified that this mechanism of action is mainly caused by Pso covalently targeting Cys106 of HMGB1, inhibiting the HMGB1-TLR4 interaction, and thereby suppressing cytokine storm generation. As the first naturally derived HMGB1 covalent inhibitor with a clear binding site, Pso plays an important role in HMGB1 induced inflammatory diseases and is an active precursor for the development of new HMGB1 covalent inhibitors.
研究领域:
药理学
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免疫学
·
呼吸病学
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DOI
PubMed
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
·
2017
·Vol. 233
·期 9
·6714-6721
·
IF 4.08
Haihong Zhou,Congli Jin,Lili Cui,Huaijie Xing,Jun Liu,Wang Liao,Haojie Liao,Yangsheng Yu
This study aimed to investigate whether HMGB1 (high mobility group box-1 protein) and receptor for advanced glycation end products (RAGE) were involved in the irradiation-induced endothelial barrier damage and their mechanism. We constructed the damage model of endothelium barrier model with bEnd.3 cells. The permeability of endothelial barrier was detected by sodium fluorescein (Na-F) permeation test, and the irradiation dose which could induce permeability transition was determined by being exposed to different irradiation doses (5, 10, 15, 20 Gy). MTT assay was applied to detect cell viability under different concentrations of HMGB1 , glycyrrhizic acid (GA, a specific inhibitor of HMGB1 ), and FPS-ZM1 (a blood-brain-barrier permeant blocker of RAGE V domain-mediated ligand binding). The expression of HMGB1 , RAGE, and related molecules involved in MAPK signaling pathway, MMP-2, MMP-9, ZO-1, and claudin 5 of differently treated groups were measured by qRT-PCR, western blot, and immunofluorescence. Cells possessed stable endothelial barrier function on 4–7 days after seeded on transwell plates. The permeability of endothelial barrier would change under at least 10 Gy radiation. Both radiation and HMGB1 treatment alone could improve the permeability. After irradiation, the expressions of HMGB1 and RAGE increased and MAPK signal pathway was activated. Meanwhile, MMP-2 and MMP-9 were overexpressed, while the expression of tight junction proteins ZO-1 and claudin 5 was decreased. Radiation could activate MAPK signaling pathway through promoting the expression of HMGB1 and RAGE, which further led to endothelial barrier injury and changed its permeability.
研究领域:
细胞生物学
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分子生物学
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医学研究
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DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
2022
·
IF 4.271
Rongzhe Zhu,Xiaochen Liu,Qiupeng Xue,Xiaoru Dong,Tianyi Zhang,Yan Jiang
Previous surveys have revealed that mirtazapine (MIR), one of the most commonly prescribed antidepressants, is associated with a higher risk of adverse cardiac events compared with other newer antidepressants. Chronic ethanol (EtOH) abuse could also lead to myocardial injuries. Concerning the common comorbidity of major depression and alcohol dependence, combined consumption of MIR and EtOH might be prevalent in patients with depression, resulting in an additive or synergistic cardiotoxic effect. To this end, the present study evaluated cardiotoxicity induced by MIR-plus-EtOH in vivo (male C57BL/6J mice) and in vitro (H9c2 cardiomyoblasts), Further research on the role of autophagy and underlying signaling pathway were carried out in H9c2 cells. We found that EtOH exacerbated MIR-induced cardiotoxicity both in vivo and in vitro . Furthermore, EtOH significantly potentiated MIR-induced dysfunctional autophagy as reflected by upregulated protein levels of LC3-II, p62, Beclin1 and LAMP-1. Pharmacological inhibition of autophagy by 3-methyladenine alleviated MIR-plus-EtOH-induced myocardial injury. High mobility group box 1 (HMGB1) is a positive regulator of autophagy. In our work, HMGB1 knockdown decreased autophagosome accumulation and boosted viability in H9c2 cells. Additionally, HMGB1 blockage markedly upregulated p-Akt/Akt and p-mTOR/mTOR levels which were suppressed in MIR-plus-EtOH treated cells. In general, the present study demonstrates that EtOH potentiates MIR-induced cardiotoxicity which might be attributed to dysfunctional autophagy via inhibiting Akt/mTOR signaling pathway, while HMGB1 knockdown might contribute to improve autophagy flux.
研究领域:
药理学
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心脏病学
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细胞生物学
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毒理学
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DOI
PubMed
高影响因子
PLoS One
·
2025
·Vol. 20
·期 5
·e0322056
·
IF 2.6
Wenyue Hou,Ting Zou,Yichao Yan,Yaolong Zhuang,Shaomei Gao,Huijun Ju,Fei Yao,Qin Yuan,Liang Zhou,Guoqiang Liang,Xiudao Song,Lurong Zhang
5-O-Methylvisammioside (5OMV), a flavonol compound derived from the traditional Chinese medicine plant Saposhnikovia divaricat , has been shown to inhibit vasospasm induced by High Mobility Group Box 1 (HMGB1) protein. However, its therapeutic potential and molecular mechanisms in HMGB1-induced tumor angiogenesis remain unexplored. Through comprehensive in vitro assays, we demonstrated that 5OMV significantly attenuates HMGB1-induced proliferation, migration, tube formation, and angiogenic activity in human umbilical vein endothelial cells (HUVECs). Parallel in vivo studies using an orthotopic hepatocellular carcinoma model in C57BL/6 mice revealed that 5OMV treatment markedly reduced tumor progression and microvascular density. Mechanistic studies identified that 5OMV downregulates both total and phosphorylated forms of RAGE, MEK, and ERK in HUVECs and tumor tissues. These findings collectively establish that 5OMV exerts anti-tumor effects in hepatocellular carcinoma through targeted modulation of the HMGB1/RAGE/MEK/ERK signaling axis.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
iScience
·
2023
·
IF 5.8
Jiapeng Hu,Ruiwei Ding,Shaozhuang Liu,Jia Wang,Jianjun Li,Yunxiao Shang
Asthma is a global chronic airway disease. The expression and role of RNF125, an E3 ubiquitin ligase, in asthma remain uncertain. In this study, we revealed that RNF125 was downregulated in the bronchial epithelium of mice and patients with asthma. Rnf125 hypermethylation was responsible for the low expression of RNF125 in primary airway epithelial cells of mice treated with OVA. Moreover, we demonstrated that RNF125 could attenuate autophagy, oxidative stress, and protect epithelial barrier in vivo and in vitro . Additionally, we identified HMGB1 as a substrate of RNF125, which interacted with the HMG B-box domain of HMGB1 and induced degradation via the ubiquitin proteasome system, reducing autophagy and oxidative stress. Overall, our findings elucidated that hypermethylation of Rnf125 reduced its expression, which promoted autophagy-induced oxidative stress in asthma by increasing HMGB1 stability. These findings offer a theoretical and experimental basis for the pathogenesis of asthma.
研究领域:
免疫学
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肺科学
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分子生物学
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表观遗传学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Jinlian Liu,Ke Song,Bingqi Lin,Zhenfeng Chen,Zirui Zuo,Yixing Fang,Qi He,Xiaodan Yao,Zhifeng Liu,Qiaobing Huang,Xiaohua Guo
Neutrophils and T lymphocytes are closely related to occurrence of immunosuppression in sepsis. Studies have shown that neutrophil apoptosis decreases and T lymphocyte apoptosis increases in sepsis immunosuppression, but the specific mechanism involved remains unclear. In the present study, we found Toll-like Receptor 2 (TLR2) and programmed death-ligand 1 (PD-L1) were significantly activated in bone marrow neutrophils of wild-type mice after LPS treatment and that they were attenuated by treatment with C29, an inhibitor of TLR2. PD-L1 activation inhibits neutrophil apoptosis, whereas programmed death protein 1 (PD-1) activation promotes apoptosis of T lymphocytes, which leads to immunosuppression. Mechanistically, when sepsis occurs, pro-inflammatory factors and High mobility group box-1 protein (HMGB1) passively released from dead cells cause the up-regulation of PD-L1 through TLR2 on neutrophils. The binding of PD-L1 and PD-1 on T lymphocytes leads to increased apoptosis of T lymphocytes and immune dysfunction, eventually resulting in the occurrence of sepsis immunosuppression. In vivo experiments showed that the HMGB1 inhibitor glycyrrhizic acid (GA) and the TLR2 inhibitor C29 could inhibit the HMGB1/TLR2/PD-L1 pathway, and improving sepsis-induced lung injury. In summary, this study shows that HMGB1 regulates PD-L1 and PD-1 signaling pathways through TLR2, which leads to immunosuppression.
研究领域:
免疫学
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传染病学
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分子生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2022
·
IF 6.1
Liyu Jiang,Yan Zeng,Leilei Ai,Hao Yan,Xiaochun Yang,Peihua Luo,Bo Yang,Zhifei Xu,Qiaojun He
The application of lapatinib , a widely used dual inhibitor of human epidermal growth factor receptor 1 (EGFR/ERBB1) and 2 (HER2/ERBB2), has been seriously limited due to cutaneous toxicity . However, the specific mechanism of lapatinib-induced cutaneous toxicity has not been clarified, leading to the lack of an effective strategy to improve clinical safety. Here, we found that lapatinib could induce mitochondrial dysfunction, lead to DNA damage and ultimately cause apoptosis of keratinocytes. In addition, we found that lapatinib could induce an aberrant immune response and promote the release of inflammatory factors in vitro and in vivo . Mechanistically, downregulated expression of the DNA repair protein HMGB1 played a critical role in these toxic reaction processes. Overexpression of HMGB1 inhibited keratinocyte apoptosis and inflammatory reactions. Therefore, restoring HMGB1 expression might be an effective remedy against lapatinib-induced cutaneous toxicity. Finally, we found that saikosaponin A could significantly rescue the reduced HMGB1 transcription, which could alleviate lapatinib-induced DNA damage, inhibit keratinocyte apoptosis and further prevent the toxicity of lapatinib in mice. Collectively, our study might bring new hope to clinicians and tumor patients and shed new light on the prevention of cutaneous adverse drug reactions induced by EGFR inhibitors.
研究领域:
肿瘤学
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药理学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGICAL SCIENCES
·
2016
·Vol. 153
·期 2
·303-315
·
IF 3.88
Fu Juanli,Shi Qiong,Song Xiufang,Liu Zixuan,Wang Yawen,Wang Yuxin,Song Erqun,Song Yang
Tetrachlorobenzoquinone (TCBQ) is a confirmed active metabolite of a well-known environmental pollutant pentachlorophenol (PCP). Unfortunately, there is insufficient knowledge present available on TCBQ’s toxicity. Our previous studies indicated that TCBQ induces inflammatory response in vivo and in vitro; however, its exact mechanism needs further investigation. Toll-like receptors (TLRs) play a crucial role in conveying of inflammatory signaling, whilst high-mobility group box 1 (HMGB1) functions as a transcription-enhancing nuclear protein that regulates inflammation. Indeed, this study demonstrated that TCBQ induces the secretion/translocation of HMGB1, which in turn activates its receptors, TLR family gene (especially TLR4) and receptor for advanced glycation end-products (RAGE) expressions. Consistently, the binding affinity of HMGB1 with its receptors also increased. In the case of HMGB1 or TLR4 deficiency, there were decreases in TCBQ-induced neuroinflammatory cytokine production and neuropathological changes, eg, neuronal loss, astrocyte and macrophage cells activation. Moreover, we found the mobilization of TLR4 into lipid rafts occurs in response to TCBQ exposure, lipid rafts disruptors weakened this effect, suggested lipid rafts play an essential role for TLR4-mediated signal transduction and target inflammatory cytokines expressions. In summary, our current findings revealed a previously unknown mechanism of TCBQ-induced neurological inflammation related to HMGB1-TLR4 signaling.
研究领域:
毒理学
·
神经科学
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免疫学
·
环境健康
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DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2025
·
IF 7.3
Zixu Li,Yacan Gong,Emmanuel Sunday Okeke,Dan Li,Yao Chen,Weiwei Feng,Ting Zhao,Liuqing Yang,Guanghua Mao,Xiangyang Wu
Typical plasticizer dibutyl phthalate (DBP) has been demonstrated to induce hepatotoxicity in zebrafish, but the underlying molecular mechanisms remain incompletely elucidated. Numerous studies have shown that ferroptosis is involved in the pathophysiological progression of hepatic disease. However, it remains unclear whether ferroptosis is involved in the DBP-induced hepatotoxicity in zebrafish. Initially, histopathological analyses have preliminarily confirmed that DBP can activate inflammatory responses in the zebrafish liver. Further investigation revealed that DBP induces ferroptosis in the zebrafish liver, characterized by iron overload, lipid peroxidation, and aberrant activation of ferroptosis pathways. Furthermore, DBP exposure induced ferroptosis, disrupting cell membranes and subsequent release of HMGB1, which are sensed by immunocytes TLR4/NF-κB signaling pathways, thereby activating the innate immune response in a context-dependent manner. Moreover, the ferroptosis inhibitor Fer-1 effectively rescues the activation of HMGB1-TLR4/NF-κB-mediated immune processes. Overall, this work enriches the molecular mechanism of DBP-induced zebrafish liver inflammatory damage and provides a reliable biomarker for future environmental risk assessment of DBP.
研究领域:
环境毒理学
·
分子生物学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death Discovery
·
2022
·Vol. 8
·期 1
·1-13
·
IF 7.109
Lian Ni,Chen Yujie,Chen Sihan,Xiao Ta,Song Changjun,Ke Yangying,Wei Xuecui,Gong Chunyan,Yu Hui,Gu Heng,Chen Qing,Li Min,Chen Xu
Keratinocyte necroptosis (with proinflammatory characteristic) is required for epidermal damage in contact hypersensitivity (CHS). In DNCB-induced CHS mice model, we observed the aggravated keratinocyte death and increased phosphorylation level of MLKL, RIPK3 and RIPK1. However, CHS skin lesion did not present in keratinocyte-specific Mlkl knockout mice. We validated that MLKL-mediated keratinocyte necroptosis is required for epidermal damage in response to immune microenvironment in CHS. Moreover, MLKL-mediated necroptosis deficiency or inhibition resulted in blocking recruitment and activation of inflammatory cells in CHS via reducing HMGB1 release in keratinocytes. This study suggests that MLKL-mediated keratinocyte necroptosis functions as a self-amplified actor in inflammatory responses and could be considered as an effective therapeutic target. It proposes an innovative prospective that inhibiting keratinocyte necroptosis can prevent the development of epidermal damage in CHS.
研究领域:
免疫学
·
细胞生物学
·
皮肤病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Sumin Ge,Sihua Wu,Qin Yin,Meng Tan,Sichuan Wang,Yonghao Yang,Zixuan Chen,Lei Xu,Hui Zhang,Chuang Meng,Yufei Xia,Naoki Asakawa,Wenping Wei,Kaizheng Gong,Xin Pan
Ethnopharmacological relevance Eclipta prostrata (Linn.) is a traditional medicinal Chinese herb that displays multiple biological activities, such as encompassing immunomodulatory, anti-inflammatory, anti-tumor, liver-protective, antioxidant, and lipid-lowering effects. Ecliptasaponin A (ESA), a pentacyclic triterpenoid saponin isolated from Eclipta prostrata (Linn.), has been demonstrated to exert superior anti-inflammatory activity against many inflammatory disorders. Aim of the study Inflammation plays a critical role in acute myocardial infarction (AMI). This study aims to explore the treatment effects of ESA in AMI, as well as the underlying mechanism. Methods An AMI mouse model was established in mice via left anterior descending coronary artery (LAD) ligation. After surgery, ESA was injected at doses of 0.5, 1.25, and 2.5 mg/kg, respectively. Myocardial infarction size, cardiomyocyte apoptosis and cardiac echocardiography were studied. The potential mechanism of action of ESA was investigated by RNA-seq, Western blot, surface plasmon resonance (SPR), molecular docking, and immunofluorescence staining. Results ESA treatment not only significantly reduced myocardial infarct size, decreased myocardial cell apoptosis, and inhibited inflammatory cell infiltration, but also facilitated to improve cardiac function. RNA-seq and Western blot analysis proved that ESA treatment-induced differential expression genes mainly enriched in HMGB1/TLR4/NF-κB pathway. Consistently, ESA treatment resulted into the down-regulation of IL-1β, IL-6, and TNF-α levels after AMI. Furthermore, SPR and molecular docking results showed that ESA could bind directly to HMGB1, thereby impeding the activation of the downstream TLR4/NF-κB pathway. The immunofluorescence staining and Western blot results at the cellular level also demonstrated that ESA inhibited the activation of the HMGB1/TLR4/NF-κB pathway in H9C2 cells. Conclusion Our study was the first to demonstrate a cardiac protective role of ESA in AMI. Mechanism study indicated that the treatment effects of ESA are mainly attributed to its anti-inflammatory activity that was mediated by the HMGB1/TLR4/NF-κB pathway.
研究领域:
药理学
·
心脏病学
·
免疫学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
2019
·
IF 3.499
Qiong Shi,Yawen Wang,Wenjing Dong,Erqun Song,Yang Song
Autophagy, which works to remove stress and maintain cellular homeostasis, is usually considered a “pro-survival” signal. Contrarily, apoptosis is programmed “pro-death” machinery. Polychlorinated biphenyls (PCBs) are a group of ubiquitous industrial pollutants. Our previous studies illustrated that a PCB quinone metabolite, PCB29-pQ, elicited both autophagy and apoptosis. However, the signaling underlying the autophagy and apoptosis cross-talk has not been characterized. Here, we found that PCB29-pQ-induced autophagy mainly occurred at a lower concentration (5 μM), while apoptosis mostly arose at a higher concentration (15 μM) in HepG2 cells. Next, we demonstrated the elevation of intracellular calcium levels and calpain activity with PCB29-pQ treatment; however, the unaffected subcellular location of truncated ATG5 and Beclin1 suggested the irrelevance of calpain towards the autophagy-to-apoptosis signaling shift. HMGB1 and p53 both serve as transcription factors that play crucial roles in the regulation of PCB29-pQ-induced autophagy and apoptosis. PCB29-pQ not only enhanced the expression of HMGB1 and p53 but also promoted their binding and cytosolic translocation. Interestingly, HMGB1 rather than p53 plays a primary role in 5 μM of PCB29-pQ-induced autophagy in the nucleus; however, p53 promoted apoptosis to a great extent in the cytosol at the dose of 15 μM PCB29-pQ. Together, HMGB1 and p53 provided a subtle balance between autophagy and apoptosis, thus determining the fate of PCB29-pQ-treated cells.
研究领域:
毒理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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